Project Summary/Abstract The NIMH F31 award will support my training in pharmacoepidemiologic research using large, complex observational databases. My long-term goal is to conduct research that helps inform the selection of pharmacologic treatments to enhance patient outcomes among those with mental and physical illness. I have the support of a multidisciplinary collaborative research team with expertise in pharmacoepidemiologic methods, multi-morbidity, diabetes, and mental health, well-suited to provide mentorship in achieving my training goals. Aligned with my long-term goal, my dissertation research will evaluate the impact of second generation antipsychotics (SGAs) on diabetes outcomes among patients with major depressive disorder (MDD) and pre-existing type II diabetes (T2DM). SGAs have recently become a more widely accepted treatment option for MDD. According to the National Ambulatory Medical Care Survey 2009-2010, 12.5% of adult non-psychotic, unipolar depression office visits resulted in a SGA prescription, an almost three-fold increase since 1999-2000. Moreover, the largest increases were among patients with comorbid diabetes, dyslipidemia, or cardiovascular disease. It is well-known that SGAs are associated with increased risk of developing diabetes; however, their impact on diabetes outcomes among patients with depression and pre-existing diabetes is not well understood. Use of SGAs is associated with increased risk of both hypoglycemia and hyperglycemia among patients 65 years and older with pre-existing diabetes. In contrast, studies among schizophrenia or bipolar disorder patients younger than 65 years have concluded that SGA use is associated with improved diabetes outcomes. Given that depression and diabetes frequently co-occur and patients with both disorders are at higher risk for all-cause and cardiovascular mortality, understanding the influence of SGAs on diabetes outcomes is highly consequential for patients, clinicians, and public health. The specific aims are to compare patient characteristics, clinical history, and treatment patterns of SGAs versus alternative second-line depression medications among adult patients 18-64 years with MDD and comorbid T2DM (Aim 1); examine the impact of SGA use compared to alternative second-line depression medications on risk of diabetes-related hospitalization or diabetes treatment intensification in this population (Aim 2); and evaluate the comparative effect of aripiprazole, quetiapine, bupropion, mirtazapine, and tricyclic antidepressants (TCAs) on time to diabetes-related hospitalization or diabetes treatment intensification among patients with MDD and comorbid diabetes (Aim 3). Additionally, we will compare the performance of full-cohort vs. subgroup-specific high dimensional propensity score (hdPS) matching algorithms when identifying exposure subgroups in the context of this study (Sub-Aim 3a).